Extraskeletal Myxoid Chondrosarcomas: The Uncommon Clinicopathologic Manifestations and Significance of TAF15::NR4A3 Fusion.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.

Epstein-Barr virus latent membrane protein-1 upregulates autophagy and promotes viability in Hodgkin lymphoma: Implications for targeted therapy.

Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed-Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are infected by Epstein-Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV-latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV-LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation-induced autophagic stress, and alleviated autophagy inhibition- or doxorubicin-induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte-predominant and lymphocyte-rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1-positive HL xenografts with better efficacy than LMP1-negative HL xenografts. Collectively, these results suggest that EBV-LMP1 enhances autophagy and promotes the viability of HL cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with HL, especially EBV-positive cases.

Frequent overexpression of klotho in fusion-negative phosphaturic mesenchymal tumors with tumorigenic implications.

Phosphaturic mesenchymal tumors (PMT) are tumors that cause hypophosphatemia/osteomalacia chiefly by secreting FGF23. We have identified FN1-FGFR1/FGF1 fusion genes in nearly half of PMT, suggesting a central role of FGFR1 pathways in the pathogenesis of PMT. Tumorigenic drivers are unknown for tumors where previous study detected neither fusion, including many in bone, where FISH failed because of tissue decalcification. To identify alternative fusions in PMT without known fusions, as well as to validate the positive FISH results and characterize the fusion junctions, 34 PMT were studied, including 12 with known FN1-FGFR1 fusion by FISH (Group A), 2 with FN1-FGF1 (B), 12 with neither fusion (C), and 8 with previous acid-based decalcification and hence unknown fusion status (D). In total, 23 archival samples were subjected to anchored multiplex PCR-based RNA-sequencing (AMP-seq) with primers targeting FN1, genes encoding the FGF/FGFR families, and KL (α-Klotho); five Group C cases were also studied with whole-transcriptomic and exome-captured RNA sequencing, respectively. The AMP-seq results were consistent with previous FISH and/or transcriptomic sequencing data, except in one old Group A sample. One case had a novel FGFR1 exon 9 breakpoint, confirmed by genomic DNA sequencing. One Group D bone tumor was found to harbor FN1-FGF1. All 3 RNA-sequencing platforms failed to identify convincing fusion genes in Group C (N = 10), which instead expressed significantly higher levels of either KL or KLB. This result was further confirmed with KL and KLB RNA CISH semi-quantification (RNAscope). Our results demonstrated the utility of AMP-seq, which was compromised by decalcification and prolonged archiving. Of potential importance, fusion-negative PMT frequently overexpressed α-Klotho (or instead ß-Klotho less commonly), whose role as an obligatory co-receptor for FGF23-FGFR1 binding suggests its aberrant expression in osteocytes/osteoblasts might result in an FGF23-FGFR1 autocrine loop that in turn drives the overexpression of FGF23 and tumorigenesis through activated FGFR pathways.

Freezing Nitrogen Ethanol Composite May be a Viable Approach for Cryotherapy of Human Giant Cell Tumor of Bone.

BACKGROUND: Liquid nitrogen has been used as adjuvant cryotherapy for treating giant cell tumor (GCT) of bone. However, the liquid phase and ultrafreezing (-196° C) properties increase the risk of damage to the adjacent tissues and may lead to perioperative complications. A novel semisolid cryogen, freezing nitrogen ethanol composite, might mitigate these shortcomings because of less-extreme freezing. We therefore wished to evaluate freezing nitrogen ethanol composite as a coolant to determine its properties in tumor cryoablation. QUESTIONS/PURPOSES: (1) Is freezing nitrogen ethanol composite-mediated freezing effective for tumor cryoablation in an ex vivo model, and if yes, is apoptosis involved in the tumor-killing mechanism? (2) Does freezing nitrogen ethanol composite treatment block neovascularization and neoplastic progression of the grafted GCTs and is it comparable to that of liquid nitrogen in an in vivo chicken model? (3) Can use of freezing nitrogen ethanol composite as an adjuvant to curettage result in successful short-term treatment, defined as absence of GCT recurrence at a minimum of 1 year in a small proof-of-concept clinical series? METHODS: The cryogenic effect on bone tissue mediated by freezing nitrogen ethanol composite and liquid nitrogen was verified by thermal measurement in a time-course manner. Cryoablation on human GCT tissue was examined ex vivo for effect on morphologic features (cell shrinkage) and DNA fragmentation (apoptosis). The presumed mechanism was investigated by molecular analysis of apoptosis regulatory proteins including caspases 3, 8, and 9 and Bax/Bcl-2. Chicken chorioallantoic membrane was used as an in vivo model to evaluate the effects of freezing nitrogen ethanol composite and liquid nitrogen treatment on GCT-derived neovascularization and tumor neoplasm. A small group of patients with GCT of bone was treated by curettage and adjuvant freezing nitrogen ethanol composite cryotherapy in a proof-of-concept study. Tumor recurrence and perioperative complications were evaluated at a minimum of 19 months followup (mean, 24 months; range, 19-30 months). RESULTS: Freshly prepared freezing nitrogen ethanol composite froze to -136° C and achieved -122° C isotherm across a piece of 10 ± 0.50-mm-thick bone with a freezing rate of -34° C per minute, a temperature expected to meet clinical tumor-killing requirements. Human GCT tissues revealed histologic changes including shrinkage in morphologic features of multinucleated giant cells in the liquid nitrogen (202 ± 45 µm; p = 0.006) and freezing nitrogen ethanol composite groups (169 ± 27.4 µm; p < 0.001), and a decreased nucleated area of neoplastic stromal cells for the 30-second treatment. Enhanced counts of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells verified the involvement of DNA fragmentation in cryoablated GCT tissues. Western blotting analysis on the expression of apoptosis regulatory proteins showed enhancement of proteocleavage-activated caspases 3, 8, and 9 and higher ratios of Bax/Bcl2 in the liquid nitrogen- and freezing nitrogen ethanol composite-treated samples. Numbers of blood vessels and human origin tumor cells also were decreased by freezing nitrogen ethanol composite and liquid nitrogen treatment in the GCT-grafted chicken chorioallantoic membrane model. Seven patients with GCT treated by curettage and adjuvant cryotherapy by use of freezing nitrogen ethanol composite preparation had no intra- or postoperative complications related to the freezing, and no recurrences during the study surveillance period. CONCLUSIONS: These preliminary in vitro and clinical findings suggest that freezing nitrogen ethanol composite may be an effective cryogen showing ex vivo and in vivo tumor cryoablation comparable to liquid nitrogen. The semisolid phase and proper thermal conduction might avoid some of the disadvantages of liquid nitrogen in cryotherapy, but a larger clinical study is needed to confirm these findings. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Investigation of Prognostic Features in Primary Cutaneous and Soft Tissue Angiosarcoma After Surgical Resection: A Retrospective Study.

Primary cutaneous and soft tissue angiosarcoma is a rare but highly aggressive malignancy. To date, surgical resection is the mainstay of treatment, but poor prognosis is expected. To investigate whether there are factors associated with poor prognosis after surgical resection and to develop a treatment guideline for current therapy, we retrospectively collected data on 28 patients who underwent surgery as initial treatment and reviewed patient demographics, tumor characteristics, disease courses, and prognoses from September 1996 to May 2013. Of these 28 patients, 17 (60.7%) were men and the mean age at first diagnosis was 66.57 ± 18.57 years. Anatomically, 17 (60.7%) tumors were in the scalp and 11 (39.3%) were in other sites of the body. Of the 28 patients, 23 (82.1%) had achieved negative surgical margins, 24 (85.7%) received adjuvant radiation therapy, and 17 (60.7%) received adjuvant chemotherapy. Twenty-one patients (75%) died during a mean follow-up time of 35.86 ± 28.91 months, and all deaths were caused by angiosarcoma. The 5-year overall survival rate was 17.86%. Sixteen (57.1%) patients had locoregional tumor recurrence, and 20 (71.4%) had distant metastases, with a median of 9.17 (range, 1.9-98.07) months to recurrence or metastasis. Possible predictors of poor prognosis (P < 0.05) in terms of disease-free survival after surgical resection were male sex, cardiovascular disease, smoking, and scalp angiosarcomas, those in terms of overall survival were older than 70 years, male sex, cardiovascular disease, smoking, scalp angiosarcomas, distant metastases, and not receiving adjuvant chemotherapy. In conclusion, although multimodal treatments are used, the overall prognosis after surgical resection is still poor, especially for patients with the above predictive factors. An early diagnosis and complete resection of the primary tumor with or without adjuvant radiotherapy and chemotherapy are suggested for a potential better outcome. For those who have a diffuse lesion pattern with the involvement of vital structures, recurrence, or metastasis, palliative resection could be an alternative treatment choice.

Prognostic factors of primary resected retroperitoneal soft tissue sarcoma: Analysis from a single asian tertiary center and external validation of gronchi's nomogram.

BACKGROUND: Surgery is the potentially curative treatment for retroperitoneal sarcoma (RS), but complete resectability is frequently a challenge. This study aimed to characterize the clinical features, prognostic factors and treatment outcomes. METHODS: A cohort of 144 patients with RS was surveyed retrospectively from January 1st, 2000 to July 30th, 2011. The prognostic influence of clinicopathological characteristics as well as treatments on local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS), were examined by univariate and multivariate analyses. A histology-specific nomogram developed by Gronchi et al was used for validation. RESULTS: Liposarcoma, leiomyosarcoma, and malignant peripheral sheath tumor (MPNST) were the most common histologies (70%). Multivariate analysis revealed FNCLCC tumor grade was the most significant prognostic factor for OS (P = 0.001) and DMFS (P < 0.001) and complete resection was the only significant prognostic factor for LRFS (P = 0.043). Incomplete resection of grade 3 tumor was significantly associated with a worse OS. Despite some differences in characteristics between our patients and Gronchi's cohort, external validation of Gronchi's nomogram demonstrated excellent concordance in predicting survival. CONCLUSIONS: Our study demonstrated tumor grade and surgical margins had significant prognostic influence and the Gronchi's nomogram has an excellent applicability in predicting survival of STS patients. J. Surg. Oncol. 2016;113:355-360. © 2016 Wiley Periodicals, Inc.

Experience of pediatric osteosarcoma of the extremity at a single institution in Taiwan: prognostic factors and impact on survival.

PURPOSE: To identify the prognostic factors and evaluate the impact of chemotherapy regimens on the outcomes of pediatric osteosarcoma of the extremities. METHODS: Patients younger than 18 years and diagnosed with high-grade osteosarcoma of the extremities during the period between January 2004 and December 2011 were included for retrospective analysis. Demographic characteristics and tumor features were compared between nonmetastatic and metastatic patients. Univariate analyses of overall survival (OS) and progression-free survival (PFS) were performed to evaluate the efficacy of various chemotherapy regimens. RESULTS: A total of 74 patients (58 with nonmetastatic and 16 with metastatic disease) were enrolled and treated with three protocols consisting of various cycles of high-dose methotrexate, adriamycin (doxorubicin), cisplatin, and high-dose ifosfamide (MACI regimens) during the 8-year study period. Presence of metastasis was inversely correlated with OS and PFS. Alkaline phosphatase levels at diagnosis and histologic response to preoperative chemotherapy were correlated with OS. Tumor size was correlated with PFS. The 5-year OS and PFS were 77 and 70 % for all patients, and 90.4 and 83.3 % for those with nonmetastatic osteosarcoma; and the rates were both 25 % in those with metastatic osteosarcoma. The chemotherapy regimens increased good response rates by 30 % and survival rates by 20 % compared to the outcomes in patients treated before 2004. CONCLUSIONS: Poor prognostic factors for osteosarcoma in pediatric patients were identified under homogeneous surgical and chemotherapy schemes. The four-drug regimens consisting of MACI contributed to the remarkably increased good response rates and consequent improvement in the survival rates.

Incidence patterns of primary bone cancer in taiwan (2003-2010): a population-based study.

BACKGROUND: Primary bone cancer (BC) incidence by age has not been surveyed in Asia. METHODS: The incidence patterns of nine subtypes of primary BCs registered between 2003 and 2010 were analyzed from Taiwan cancer registry data. More specific analyses were conducted within age groups (Group I: 0-24 years; Group II: 25-59 years; and Group III: 60-85+ years). RESULTS: A total of 1,238 newly diagnosed subjects were registered with an age-standardized incidence rate (ASR) of 6.70 per million person-years. Overall, osteosarcoma (OS: 45 %) was the most common, followed by chondrosarcoma (CS: 18 %), and Ewing sarcoma (ES: 8 %). The percentages of cases and ASRs for age groups I, II, and III were 36.3, 43.0, and 20.7 %, and 7.00, 5.48, and 10.28 per million, respectively. Significant male predilections were observed for all BCs combined, and the CS, chordoma, and malignant ameloblastoma subtypes. Our findings demonstrated an upward trend of 4.8 % per year over the study period, and was more significant for females (6.7 %). A significant increase in trend existed in the incidence of BC among females in Group II, and the incidence of OS and ES among females in Group I. CONCLUSIONS: This population-based study has allowed us to confidently define the incidence rates among three age groups of Taiwanese. Despite overall low rates, the upward trend in BC incidence among females may invoke a concern. The results suggest areas for further study into the underlying causes for these cancer trends.

Multifocal Papillary Thyroid Carcinomas With Discordant Molecular Drivers: Emphasizing the Morphology and Collision Tumors.

Multifocal papillary thyroid carcinomas (PTCs) are common and the majority of the tumors harbor mutual BRAF p.V600E mutation. This study aimed to investigate a contemporary series of multifocal PTCs with discordant molecular drivers. Consecutive thyroidectomies diagnosed with multifocal PTCs ≥0.5 cm between 2019 and 2023 were reviewed. Immunohistochemistry (IHC) for BRAF VE1 was performed for all tumors. Cases with discordant BRAF IHC results or morphologic discrepancy were identified, and BRAF IHC-negative tumors were subjected to RAS Q61R IHC and/or targeted RNA next-generation sequencing. A total of 770 patients with a main PTC ≥0.5 cm were identified; 255 (33.1%) had multifocal disease, and 142 (18.4%) had at least another PTC ≥0.5 cm. Among them, 13 cases (9.2%, 13/142) had discordant molecular drivers. Twelve cases had one or more BRAF-positive PTCs accompanied by a BRAF-negative PTC (3 with CCDC6::RET fusion, 1 with NCOA4::RET fusion, 1 with ACBD5::RET fusion, 2 with ETV6::NTRK3 fusion, 1 with TG::FGFR1 fusion, 1 with LMTK2::BRAF fusion, 1 with AGK::BRAF fusion and RAS p.Q61R mutation, 1 with RAS p.Q61R mutation, and 1 without detectable molecular drivers). The last case had tumors with discordant fusion drivers (VIM::NTRK3 and TNS1::BRAF). Most cases showed tumors that were morphologically distinct (92.3%, 12/13) and occurred in the contralateral lobes (76.9%, 10/13). Notably, we identified 4 cases (30.8%) that presented as collision tumors and 6 cases (46.2%) that showed lymph node metastases, including 2 with simultaneous involvement by tumors with discordant molecular drivers, as novel findings. In summary, a subset (9.2%) of multifocal PTCs had discordant molecular drivers and 84.6% of them were a combination of BRAF-positive and kinase gene fusion-associated PTCs, most with distinct morphologies. Almost half of the cases had nodal metastasis and a third of them showed simultaneous involvement by tumors with discordant molecular drivers. The results highlight the clinical importance of identifying such cases, given the potentially different treatments.

Minimally Required Personal Protective Equipment during Local Anesthesia Surgery in COVID-19: A Simulation Study.

In the era of the coronavirus disease 2019 (COVID-19) pandemic, surgeons and medical staff are often at a high risk of infection in the operating room, especially when the patient is spontaneously breathing. In this study, we examined the minimum requirements for personal protective equipment with double surgical masks to potentially reduce unnecessary waste of supplies. Methods: Two mannequins were each connected to a test lung machine simulating a surgeon and patient with spontaneous breathing. An aerosol generator containing severe acute respiratory syndrome coronavirus 2 virion particle substitutes was connected to the patient mannequin. The sampling points for the target molecules were set at different distances from the patient mannequin and sent for multiplex quantitative polymerase chain reaction analysis. Three clinical scenarios were designed, which differed in terms of the operating room pressure and whether a fabric curtain barrier was installed between the mannequins. Results: Analysis of the multiplex quantitative polymerase chain reaction results showed that the cycle threshold (Ct) value of the target molecule increased as the distance from the aerosol source increased. In the negative-pressure operating room, the Ct values were significantly increased at all sample points compared with the normal pressure room setting. The Ct value sampled at the surgeon mannequin wearing double face masks was significantly increased when a cloth curtain barrier was set up between the two mannequins. Conclusion: Double surgical masks provide elementary surgeon protection against COVID-19 in a negative pressure operating room, with a physical barrier in place between the surgeon and patient who is spontaneously breathing during local anesthesia or sedated surgery.

Follow-up after primary treatment of soft tissue sarcoma of extremities: impact of frequency of follow-up imaging on disease-specific survival.

BACKGROUND AND OBJECTIVES: We explored the impact of frequency of surveillance imaging on disease-specific survival (DSS) in patients with extremity soft tissue sarcoma (STS). METHODS: Locoregional imaging (LRI) and chest imaging (CI) were used to detect local recurrence (LR) and distant metastasis (DM), respectively. Relapsing patients were retrospectively assigned to more frequent surveillance (MFS) or less frequent surveillance (LFS) groups, according to the median interval for each follow-up modality. Outcome measures included overall DSS (O-DSS), post-LR DSS, and post-DM DSS. RESULTS: We assigned 165 patients to three distinct risk groups according to tumor size (≤5 vs. >5 cm), depth (superficial- vs. deep-seated), grade (I vs. II or III), and surgical margin (≥10 vs. <10 mm). Data for 80 patients who relapsed were analyzed. Among 50 high-risk (with all four risk factors) relapsing patients, those in the MFS group for either LRI or CI had better O-DSS (LRI, median 44.07 vs. 27.43 months, P = 0.008; CI, median 43.60 vs. 36.93 months, P = 0.036), post-LR DSS (median 27.20 vs. 10.63 months, P = 0.028) and post-DM DSS (median 13.20 vs. 6.24 months, P = 0.031). CONCLUSION: More frequent follow-up were associated with improved survival in high-risk relapsing patients with extremity STS by providing greater opportunities for adequate reoperation.

Prevalence and prognostic influence of genomic changes of EGFR pathway markers in synovial sarcoma.

BACKGROUND: We aimed to study the prevalence and prognostic influence of epidermal growth factor receptor (EGFR) and its downstream effectors in synovial sarcoma (SS). OBJECTIVES AND METHODS: The tissue blocks from 30 patients were obtained. Expression of EGFR and phosphatase and tensin homolog (PTEN) were examined by immunohistochemistry, and mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) exon 15, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA) exons 9, 20, and PTEN exons 5-9 were analyzed by direct sequencing. RESULTS: EGFR overexpression and PTEN deletion were found in 63.3% and 46.7% of patients. Sequence analysis failed to demonstrate mutations of KRAS and BRAF. However, an E545A point mutation in exon 9 of PI3KCA was found in 2 of the 30 (6.7%) cases and 4 point mutations in exon 5 (E99K, D106N), intro 6 to exon 7 (AATA(G)), and exon 9 (A359T) of PTEN were found in 2 of the 30 (6.7%) cases. PTEN loss was significantly more frequent in cases of trunk tumors, and the overexpression of EGFR was significantly more prevalent in patients who were 35 or older. CONCLUSIONS: PTEN deletion was associated with poor survival.

Brain, the last fortress of sarcoma: similar dismal outcome but discrepancy of timing of brain metastasis in bone and soft tissue sarcoma.

BACKGROUND AND OBJECTIVE: Brain metastasis is a rare but dismal event in sarcomas. However, the pattern of occurrence and the prognostic factors associated with post-brain metastasis survival (PBMS) are not yet well-characterized. METHODS: Sarcoma patients treated at one institute within 10-year period were retrospectively reviewed and those with brain metastasis were identified. The incidence of brain metastasis was demonstrated by case per person-years and cumulative incidence curves. Univariate factors associated with PBMS were analyzed. RESULTS: Among 611 sarcoma patients, 20 (3.3%) developed brain metastasis. Alveolar soft part sarcoma (ASPS) and osteosarcoma were the most common subtypes. Overall, the cumulative incidence was 3.9% at 5 years and 8.4% at 10 years. However, the incidence in STS patients continued to rise up to 10 years after primary diagnosis, whereas it reached a plateau in bone sarcoma patients at 3 years. Median PBMS was 1.67 months. Univariate factors associated with better PBMS included ASPS histology, initial surgical treatment, and brain irradiation for non-surgically treated patients. CONCLUSION: Our study revealed a discrepancy in the timing of occurrence of brain metastasis between STS and bone sarcoma. However, patients with brain metastasis had a poor prognosis, implicating the brain as the last fortress of sarcoma.

PML protein as a prognostic molecular marker for patients with esophageal squamous cell carcinomas receiving primary surgery.

BACKGROUND AND OBJECTIVES: We evaluated the clinicopathological associations and prognostic implications of promyelocytic leukemia gene (PML) expressions in patients with esophageal squamous cell carcinomas (ESCC) receiving primary surgery. METHODS: Expression patterns of PML and tumor protein 53 (TP53) of 132 cases of ESCC were evaluated by immunohistochemistry and correlated with clinicopathological parameters. The Cox proportional hazards model was used to determine the prognostic influence of clinicopathological factors on progression-free survival (PFS) and overall survival (OS). RESULTS: Forty-two cases (31.82%) were classified as lost expression of PML, 25 (18.94%) as focally positive, and 65 (49.24%) as diffusely expressed. Sixty-three cases (47.73%) were classified as over-expression of TP53. High expression of TP53 and down-regulation of PML were often found in advanced disease; and, in together with high pathological staging, grading, and positive margin, were associated with poor survival. However, only tumor differentiation (P = 0.016), distant metastasis (P = 0.001), and PML expression (P = 0.001) could act as independent prognostic factors for PFS, and LN metastasis (P = 0.004), TP53 (P = 0.006), and PML expression (P = 0.029) were identified as independent prognostic factors for OS in multivariate analysis. CONCLUSIONS: Our study demonstrated PML protein as an independent prognostic marker for patients with ESCC receiving primary surgery.

Ossifying low grade endometrial stromal sarcoma with PHF1-BRD8 fusion.

Low-grade endometrial stromal sarcoma and ossifying fibromyxoid tumors are two types of mesenchymal tumors that share no similarities in terms of site, sex, and morphological characteristics. They are rare, low grade tumors of uncertain lineage, with no definite immunological markers. Interestingly, a common PHF1 gene- related rearrangement was observed in these two tumors. Here, we report a case of endometrial stromal sarcoma with distinct ossification. Microscopically, the tumor is composed of bland-looking ovoid cells with low cellularity in the fibromyxoid stroma. Foci of metaplastic bone formation were noted. Using a combination of FISH, transcriptome sequencing, and molecular techniques, we identified a new PHF1-BRD8 fusion transcript, which was previously described, but in its reciprocal fusion form. This case expands the current understanding of low-grade endometrial stromal sarcoma and emphasizes the importance of molecular characterization of unique fusion, which may be related to its distinct morphological features and the possibly chemosensitive target.

Soft tissue sarcoma of extremities: the prognostic significance of adequate surgical margins in primary operation and reoperation after recurrence.

BACKGROUND: Adult soft tissue sarcomas (STS) of extremities are prone to recurrence despite apparently complete resection. This study aimed to explore the impact of clinicopathological factors on outcome and to define an "oncological safe margin" in these patients. METHODS: A total of 181 patients with extremity STS were enrolled in a retrospective study. The prognostic influence of margin status and other clinicopathological characteristics on local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-specific survival (DSS), were examined by univariate and multivariate analyses. The influence of surgical margins on postrecurrence survival (PRS) of patients undergoing reoperation for relapsed lesions during follow-up was analyzed by the Kaplan-Meier method. RESULTS: Surgical margin width <10 mm and deep tumor depth at primary operation were consistently statistically significant independent adverse factors for LRFS, DMFS, and DSS. Patients with liposarcoma or low grade tumors had significantly higher chances of achieving adequate margins. Of 83 patients who experienced recurrence or metastasis, 53 (63.9%) received reoperation for their relapsed lesions. Patients who achieved microscopically negative margins (R0) at reoperation had significantly better PRS than those who did not (P < 0.007). Overall, patients with no recurrences had the best DSS, while relapsed patients receiving R0 reoperation had better DSS than those receiving either non-R0 reoperation or no reoperation at all. CONCLUSION: Surgical margins prognostically influence survival in both patients undergoing primary surgery and those undergoing reoperation for relapse of extremity STS. In primary surgery, the chance of achieving adequate margin may reflect the underlying aggressiveness of tumors.

Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease.

OBJECTIVE: To provide strategies for monitoring and treating severe lung involvement in Gaucher disease. STUDY DESIGN: We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. RESULTS: His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of ß-glucocerebrosidase were reported in three months. CONCLUSION: This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

Ultrasonographic and MR findings of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma, commonly occurring in children and adolescents. The tumor mostly involves the lower extremities. The prognosis of the patient depends on whether there is metastasis. We present a 19-year-old female with ASPS in her right lower leg. Grayscale and color Doppler ultrasound showed a well-defined hypoechoic lesion with hypervascularity and very low resistive index (RI). Magnetic resonance imaging revealed iso signal intensity to muscle on T1-weighted images, high signal intensity to muscle on T2-weighted images with signal voids, and good enhancement after gadolinium administration. In a mass with hypervascularity and very low RI on sonography and hypervascularity with flow voids on magnetic resonance imaging, ASPS should be considered.

Different and identical features of chondroblastic osteosarcoma and chondrosarcoma: highlights on radiography and magnetic resonance imaging.

BACKGROUND: To identify the different and identical features of 2 tumors with similar pathologic findings, chondroblastic osteosarcoma (OGS) and chondrosarcoma (CSA), with highlights on radiography and magnetic resonance imaging (MRI). METHODS: Ten patients with chondroblastic OGS and 10 patients with CSA were enrolled. After recording the tumor location, tumor morphology was evaluated for patterns of bony destruction, visible tumor matrix, and aggressive periosteal reactions, endosteal scalloping, cortical expansion, cortical breakthrough and pathologic fracture by radiographic analysis. Signal intensity changes, enhancement pattern, and tumor extensions were evaluated by MRI. RESULTS: The mean patient ages were 24.7 and 56.7 years in patients with chondroblastic OGS and CSA, respectively (p = 0.001). Tumor occurrence was detected in the appendicular bones in 8 chondroblastic OGS and 3 CSA. Three chondroblastic OGS occurred around the knee (p = 0.003). In addition, there were 6 tumors arising from the metaphysis and 2 arising from the diaphysis in chondroblastic OGS patients. In CSA patients, 1 tumor arose in the metaphysis, 1 in the diaphysis, and 1 in the epiphysis (p = 0.039). On radiographs, visible bone-forming tumor matrix was present in 8 chondroblastic OGS, and coexistence of bone- and cartilage-forming patterns were detected in 2. Visible cartilage-forming tumor matrix was present in 7 CSA, and atypical radiodensity patterns were detected in 2 (p < 0.001). Aggressive periosteal reaction was present in 7 chondroblastic OGS, and non-aggressive periosteal reaction was found in 1 CSA (p = 0.008). MRI revealed the presence of a lobular structure of high signal intensity on T2-weighted images, and peripheral rim and septal enhancement pattern was noted in 2 chondroblastic OGS and 10 CSA patients. Inhomogeneous and marginal enhancement patterns were noted in 6 and 2 chondroblastic OGS, respectively (p = 0.001). CONCLUSION: Metaphysis origin, bone-forming tumor matrix, aggressive periosteal reaction, and young patient age favored chondroblastic OGS. Some chondroblastic OGS showed radiologic and MRI appearances that were typical of CSA.

Gene amplification and tumor grading in parosteal osteosarcoma.

BACKGROUND: Parosteal osteosarcoma (POS) is a unique low grade osteosarcoma. Two separate oncogenes, MDM2 and CDK4, are specifically amplified in POS. Its clinical behavior is usually indolent. In some occasions, it may progress to high grade and become fatal. Malignant transformation with high grade differentiation is the most reliable indicator to predict its aggressiveness and metastatic potential. This study is to discover the relationship between gene amplification and grading. METHODS: Retrospective analysis of MDM2/CDK4 expression/amplification using immunostaining, multiplex quantitative polymerase chain reaction (MQPCR) and fluorescence in situ hybridization (FISH) were studied on 14 patients with recurrent POS. RESULTS: Forty tumor specimens in formalin-fixed paraffin-embedded blocks from 14 patients of POS were included in this study. Twenty-seven tumors are low-grade, 13 are high-grade. All POS showed increased expression of both MDM2 and CDK4 proteins, but not those from conventional osteosarcoma. Except some tumors were non-informative (poor DNA quality), the rest of POS had a marked increase of MDM2 and CDK4 genes copies by MQPCR, and confirmed by MDM2 FISH. Moreover, the folds of amplification increase as tumors progress. And, the amplification folds in high-grade POS are consistently higher than those of conventional ones. CONCLUSION: FISH and MQPCR are both useful assays for estimating oncogene amplification status in bone tumors. Amplification levels of MDM2 and CDK4 are related to tumor grading and progression. Molecular determination of gene amplification status can be a reliable alternative for predicting clinical behavior of POS at small biopsies.